Actively Targeted Delivery of Doxorubicin to Bone Metastases by a pH-Sensitive Conjugation

被引:15
|
作者
Ye, Wei-Liang [1 ]
Zhao, Yi-Pu [1 ]
Na, Ren [2 ]
Li, Fei [1 ]
Mei, Qi-Bing [3 ]
Zhao, Ming-Gao [3 ]
Zhou, Si-Yuan [1 ]
机构
[1] Fourth Mil Med Univ, Sch Pharm, Dept Pharmaceut, Xian 710032, Peoples R China
[2] West Changle Sanat Xian Army Retired Cadres Fourt, Xian 710032, Peoples R China
[3] Fourth Mil Med Univ, Sch Pharm, Dept Pharmacol, Xian 710032, Peoples R China
关键词
bone-targeted drug delivery; doxorubicin; controlled release; alendronate; conjugaton; p-glycoprotein; cytotoxicity; imaging methods; cancer; BREAST-CANCER PATIENTS; ZOLEDRONIC ACID; TUMOR-GROWTH; ALENDRONATE; BISPHOSPHONATES; NANOPARTICLES; ACIDIFICATION; MECHANISMS; RESORPTION; RESISTANCE;
D O I
10.1002/jps.24476
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Alendronate-monoethyl adipate-(hydrazone)-doxorubicin conjugate (ALN-MA-hyd-DOX) was synthesized to specifically deliver doxorubicin (DOX) to bone tumor tissue. The binding kinetics of ALN-MA-hyd-DOX with hydroxyapatite (HA) and natural bone were detected by using spectrophotometer. Cytotoxicity of ALN-MA-hyd-DOX on tumor cells was determined by MTT [3-(4,5-dimethylthiaol-2-yl)-2,5-diphenyl-tetrazolium bromide] method. The cellular uptake of ALN-MA-hyd-DOX was observed by using fluorescence microscopy. The in vivo antitumor activity of ALN-MA-hyd-DOX was investigated by using tumor-bearing nude mice model. The results indicated that ALN-MA-hyd-DOX was able to quickly bind with HA and natural bone. ALN-MA-hyd-DOX immobilized on the natural bone released more DOX in pH 5.0 medium than that in pH 6.0 or 7.4 medium. The cytotoxicity of ALN-MA-hyd-DOX toward A549 cells and MDA-MB-231/ADR cells was greater than DOX. ALN-MA-hyd-DOX was rapidly uptaken by A549 cells and MDA-MB-231/ADR cells. Compared with the same dose of free DOX, ALN-MA-hyd-DOX significantly decreased tumor volume of tumor-bearing nude mice. DOX mainly distributed in bone tumor tissue after ALN-MA-hyd-DOX was intravenously administered to tumor-bearing nude mice, whereas DOX distributed through the whole body after DOX was intravenously administered to tumor-bearing nude mice. These findings implied that the ALN-MA-hyd-DOX was a promising bone-targeted conjugate for treating bone neoplasms. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2293-2303, 2015
引用
收藏
页码:2293 / 2303
页数:11
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